Project Summary Female infertility due to disorders of androgen excess or insufficiency is a growing problem in the U.S. and worldwide with high mental and financial costs. Androgen imbalance is implicated in polycystic ovary syndrome and ovarian insufficiency; however, while the phenotypic effects of androgen activity in the ovary have been described, little is known about the molecular pathways underlying these effects. This fellowship project will provide a path for a highly qualified candidate with a combined MD/PhD degree into a career in reproductive science as an independent investigator. The research proposal focuses on non-classical extranuclear activity of androgen receptor in ovarian granulosa cells and the role of paxillin, a mediator of steroid signaling in many contexts. The mechanism of paxillin in androgen-mediated enhanced granulosa cells responsiveness to follicle- stimulating hormone will be elucidated in cultured cells. The effects of paxillin loss in granulosa cells on follicular development and fertility will be examined in an ovary-specific knockout mouse model. The hypothesis is that the cytoplasmic adaptor protein paxillin orchestrates crosstalk between androgen-mediated kinase signaling, transcription regulation and cytoskeletal remodeling in granulosa cells. This places paxillin at the center of the complex processes underlying granulosa cell adaptation to the rapidly changing steroid hormone microenvironment during follicular development. The Hammes laboratory has an extensive background in reproduction, mouse genetics, steroid signaling, and kinase signaling, providing the applicant a unique opportunity to address these questions. In addition, the applicant has assembled an advisory committee comprised of world experts in ovarian kinase signaling and paxillin. Her training plan includes an intensive off- site course in state-of-the-science reproductive research techniques titled ?Frontiers in Reproduction?, in addition to University-sponsored courses in ethics, leadership and professional development, as well as research seminars, national meetings and one-on-one instruction. During this fellowship, the applicant aims to develop science communication and mentorship skills and transition to early independence as a physician scientist. She has positioned herself optimally to achieve these goals under the mentorship of Dr. Hammes, a role model physician scientist with a long track record of training successful investigators in basic and translational research. The institutional environment at URMC and its Endocrine Division prioritizes collaboration in research and medicine and is invested in the success of early career scientists. The NIH-supported Clinical and Translational Science Institute will be instrumental in the applicant?s development and early career funding. The knowledge gained from the studies proposed in this fellowship will advance our understanding of androgen activity in the ovary and the pathogenesis of infertility due to either insufficiency or excess of androgens in women. The training plan capitalizes on the applicant?s strong research background and long-standing interest in female fertility.